Franke T F, Kaplan D R, Cantley L C, Toker A
ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research Facility and Development Center (NCI-FCRFDC), Frederick, MD 21702, USA.
Science. 1997 Jan 31;275(5300):665-8. doi: 10.1126/science.275.5300.665.
The regulation of the serine-threonine kinase Akt by lipid products of phosphoinositide 3-kinase (PI 3-kinase) was investigated. Akt activity was found to correlate with the amount of phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P2) in vivo, and synthetic PtdIns-3,4-P2 activated Akt both in vitro and in vivo. Binding of PtdIns-3,4-P2 occurred within the Akt pleckstrin homology (PH) domain and facilitated dimerization of Akt. Akt mutated in the PH domain was not activated by PI 3-kinase in vivo or by PtdIns-3, 4-P2 in vitro, and it was impaired in binding to PtdIns-3,4-P2. Examination of the binding to other phosphoinositides revealed that they bound to the Akt PH domain with much lower affinity than did PtdIns-3,4-P2 and failed to increase Akt activity. Thus, Akt is apparently regulated by the direct interaction of PtdIns-3,4-P2 with the Akt PH domain.
研究了磷酸肌醇3激酶（PI 3激酶）的脂质产物对丝氨酸 - 苏氨酸激酶Akt的调节作用。发现Akt活性与体内磷脂酰肌醇 - 3,4 - 二磷酸（PtdIns - 3,4 - P2）的量相关，并且合成的PtdIns - 3,4 - P2在体外和体内均能激活Akt。PtdIns - 3,4 - P2的结合发生在Akt普列克底物蛋白同源（PH）结构域内，并促进Akt的二聚化。在PH结构域发生突变的Akt在体内不能被PI 3激酶激活，在体外也不能被PtdIns - 3,4 - P2激活，并且其与PtdIns - 3,4 - P2的结合受损。对其与其他磷酸肌醇结合的研究表明，它们与Akt PH结构域的结合亲和力远低于PtdIns - 3,4 - P2，并且不能增加Akt活性。因此，Akt显然是通过PtdIns - 3,4 - P2与Akt PH结构域的直接相互作用来调节的。
